The present invention relates to a novel and economical process for preparing (S,S)-2,8-diazabicyclo[4.3.0]nonane of formula I-a, a valuable intermediate used for constructing quinolone and naphthyridine derivatives having antibacterial effectiveness, e.g. moxifloxacin, and its enantiomer I-b.

The preparation of (S,S)-2,8-diazabicyclo[4.3.0]nonane of formula I-a is showing in scheme 1.
The intermediate, racemic cis-(S,S/R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane of formula IV described in EP 0350733B1 is prepared via the coupling of pyridine-2,3-dicarboxylic acid with benzylamine to form 6-benzyl-pyrrolo[3,4-b]pyridine-5,7-dione of formula II, followed by de-aromatization via catalytic hydrogenation to generate formula III and LAH reduction to remove di-carbonyl groups.

To obtain the desired enantiomer the racemic IV needs to be separated. Two methods for the resolution are disclosed by EP 0550903 and U.S. Pat. No. 5,480,879.
One method is using nature L-(+)-tartaric acid as resolution agent and DMF, an expensive solvent, as resolution solvent. The desired enantiomer of (S,S)-benzylpyrrolopiperidine L-(+)-tartrate of formula V is crystallized out subsequently from racemic cis-(S,S/R,R)-8-benzyl-2,8-diazabicyclo[4.3.0]nonane tartrate solution since undesired R,R-enantiomer salt is required prior removal.
Alternatively, the S,S-enantiomer salt can precipitate first if D-(−)-tartaric acid is used. But, the application of the second method to the manufacture can be ruled out owing to the high cost of the unnatural D-(−)-tartaric acid.
By using same resolution reagent, L-(+)-tartaric acid, U.S. Pat. No. 6,235,908 makes improvement on the resolution method for the same intermediate of formula IV, wherein expensive DMF is replaced by 1-butanol or an alcohol/water solvent mixture.
The desired S,S-enantiomer of formula V from separation is then subjected to remove benzyl group by catalytic hydrogenation to give the title compound (S,S)-2,8-diazabicyclo[4.3.0]nonane of formula I-a.
U.S. Pat. No. 5,770,597 discloses a different approach to prepare racemic mixture of cis-(S,S/R,R)-2,8-diazabicyclo[4.3.0]nonane of formula IX as showing in scheme 2.

The first step, alkylation on toluene-4-sulfonamide with 2,3-dichloromethylpyridine of formula VI is performed following the method released by W. L. F. Armarego et al in J. Chem. Soc. Perkin Trans. 1, 2485 (1972) to form 2,3-dihydro-2-p-toluene sulfonyl-1H-pyrrolo[2,3,c]pyridine of formula VII, which is treated with HBr/HAc to remove toluene-sulfonyl group instructed by the method of Weisblat et al published in J. Am. Chem. Soc. 75, 3630 (1953) to form the compound VIII. And finally, the catalytic hydrogenation reduces pyridine ring of formula VIII to give cis-(S,S/R,R)-2,8-diazabicyclo[4.3.0]nonane of formula IX as a racemic mixture.
The disadvantages of the method is that the first reaction carrying on in slurry formed by DMF and NaH. NaH is a reagent of difficult to be handling and working up. Hydrogen gas is generated during whole reaction period. Furthermore, NaH and DMF mixture system has been reported to cause explosive accidents many times. Therefore, there is less practical value for the manufacture. Obviously, the route is permitted only for preparing the racemate.